The use of electrical stimulation to enhance recovery following peripheral nerve injury.

Peripheral nerve injury is common and can have devastating consequences. In severe cases, functional recovery is often poor despite surgery. This is primarily due to the exceedingly slow rate of nerve regeneration at only 1-3 mm/day. The local environment in the distal nerve stump supportive of nerve regrowth deteriorates over time and the target end organs become atrophic. To overcome these challenges, investigations into treatments capable of accelerating nerve regrowth are of great clinical relevance and are an active area of research. One intervention that has shown great promise is perioperative electrical stimulation. Postoperative stimulation helps to expedite the Wallerian degeneration process and reduces delays caused by staggered regeneration at the site of nerve injury. By contrast, preoperative "conditioning" stimulation increases the rate of nerve regrowth along the nerve trunk. Over the past two decades, a rich body of literature has emerged that provides molecular insights into the mechanism by which electrical stimulation impacts nerve regeneration. The end result is upregulation of regeneration-associated genes in the neuronal body and accelerated transport to the axon front for regrowth. The efficacy of brief electrical stimulation on patients with peripheral nerve injuries was demonstrated in a number of randomized controlled trials on compressive, transection and traction injuries. As approved equipment to deliver this treatment is becoming available, it may be feasible to deploy this novel treatment in a wide range of clinical settings.

Building a Bridge to Community: A Pragmatic Randomized Trial Examining a Combined Physical Therapy and Resistance Exercise Intervention for People after Head and Neck Cancer.

BACKGROUND: Established barriers to general exercise and physical activity among individuals with head and neck cancer include dry mouth, difficulty eating, weight loss, fear of injury, comorbidities, and treatment-related symptoms of pain and fatigue. METHODS/DESIGN: A 12-week pragmatic randomized controlled trial was conducted followed by an optional supported exercise transition phase. Eligible participants were individuals with head and neck cancers who had undergone surgery and/or radiation therapy to lymph node regions in the neck. Participants were randomized to a comparison group involving a shoulder and neck physiotherapeutic exercise protocol, or to a combined experimental group comprising the shoulder and neck physiotherapeutic exercise protocol and lower-body resistance exercise training. The primary outcome of this study was fatigue-related quality of life. RESULTS: Sixty-one participants enrolled, 59 (97%) completed the randomized trial phase, 55 (90%) completed the 24-week follow-up, and 52 (85%) completed the one-year follow-up. Statistically significant between-group differences were found in favor of the combined experimental group for the fatigue-related quality of life, fitness outcomes, and overall physical activity. Paired comparisons confirmed significant within-group improvements for both groups from baseline to one-year follow-up across most outcomes. DISCUSSION: A group-based combined physiotherapeutic and lower-body resistance exercise program was feasible and effective. Findings are limited to individuals who had undergone a surgical neck dissection procedure. Given the complexity of head and neck cancer, further pragmatic interdisciplinary research is warranted.

Barriers to Surgical Intervention and Factors Influencing Motor Outcomes in Patients with Severe Peripheral Nerve Injury: A Province Wide Cohort Study.

INTRODUCTION: Despite the importance of timing of nerve surgery after peripheral nerve injury, optimal timing of intervention has not been clearly delineated. The goal of this study is to explore factors that may have a significant impact on clinical outcomes of severe peripheral nerve injury that requires reconstruction with nerve transfer or graft. MATERIALS AND METHODS: Adult patients who underwent peripheral nerve transfer or grafting in Alberta were reviewed. Clustered multivariable logistic regression analysis was used to examine the association of time to surgery, type of nerve repair, and patient characteristics on strength outcomes. Cox proportional hazard regression analysis model was used to examine factors correlated with increased time to surgery. RESULTS: Of the 163 patients identified, the median time to surgery was 212 days. For every week of delay, the adjusted odds of achieving Medical Research Council strength grade ≥ 3 decreases by 3%. An increase in preinjury comorbidities was associated with longer overall time to surgery (aHR 0.84, 95% CI 0.74-0.95). Referrals made by surgeons were associated with a shorter time to surgery compared to general practitioners (aHR 1.87, 95% CI 1.14-3.06). In patients treated with nerve transfer, the adjusted odds of achieving antigravity strength was 388% compared to nerve grafting; while the adjusted odds decreased by 65% if the injury sustained had a pre-ganglionic injury component. CONCLUSION: Mitigating delays in surgical intervention is crucial to optimizing outcomes. The nature of initial nerve injury and surgical reconstructive techniques are additional important factors that impact postoperative outcomes.

Characterization of Spinal Cord Injury Patients for Arm Functional Restoration through Nerve Transfer.

INTRODUCTION: Traumatic spinal cord injuries (tSCI) are common, often leaving patients irreparably debilitated. Therefore, novel strategies such as nerve transfers (NT) are needed for mitigating secondary SCI damage and improving function. Although different tSCI NT options exist, little is known about the epidemiological and injury-related aspects of this patient population. Here, we report such characteristics to better identify and understand the number and types of tSCI individuals who may benefit from NTs. MATERIALS AND METHODS: Two peripheral nerve experts independently evaluated all adult tSCI individuals < 80 years old admitted with cervical tSCI (C1-T1) between 2005 and 2019 with documented tSCI severity using the ASIA Impairment Scale for suitability for NT (nerve donor with MRC strength ≥ 4/5 and recipient ≤ 2/5). Demographic, traumatic injury, and neurological injury variables were collected and analyzed. RESULTS: A total of 709 tSCI individuals were identified with 224 (32%) who met the selection criteria for participation based on their tSCI level (C1-T1). Of these, 108 (15% of all tSCIs and 48% of all cervical tSCIs) were deemed to be appropriate NT candidates. Due to recovery, 6 NT candidates initially deem appropriate no longer qualified by their last follow-up. Conversely, 19 individuals not initially considered appropriate then become eligible by their last follow-up. CONCLUSION: We found that a large proportion of individuals with cervical tSCI could potentially benefit from NTs. To our knowledge, this is the first study to detail the number of tSCI individuals that may qualify for NT from a large prospective database.

'Inlay' Regenerative Peripheral Nerve Interface (RPNI) is superior to 'Burrito' RPNI for successful treatment of rat neuroma pain.

SUMMARY: Treatment of painful neuromas has long posed a significant challenge for peripheral nerve patients. The Regenerative Peripheral Nerve Interface (RPNI) provides the transected nerve with a muscle graft target to prevent neuroma formation. Discrepancies in the RPNI surgical techniques between animal models (Inlay-RPNI) versus clinical studies (Burrito-RPNI) preclude direct translation of results from bench to bedside and may account for variabilities in patient outcomes. We compared outcomes of these two surgical techniques in a rodent model. Animals treated with the Burrito-RPNI after tibial nerve neuroma formation demonstrated no improvement in pain assessment, and tissue analysis revealed complete atrophy of the muscle graft with neuroma recurrence. By contrast, animals treated with the Inlay-RPNI had significant improvements in pain with viable muscle grafts. Our results suggest superiority of the Inlay-RPNI surgical technique for the management of painful neuroma in rodents.

A Direct Comparison of Targeted Muscle Reinnervation and Regenerative Peripheral Nerve Interfaces to Prevent Neuroma Pain.

BACKGROUND AND OBJECTIVES: Targeted muscle reinnervation (TMR) and regenerative peripheral nerve interface (RPNI) surgeries manage neuroma pain; however, there remains considerable discord regarding the best treatment strategy. We provide a direct comparison of TMR and RPNI surgery using a rodent model for the treatment of neuroma pain. METHODS: The tibial nerve of 36 Fischer rats was transected and secured to the dermis to promote neuroma formation. Pain was assessed using mechanical stimulation at the neuroma site (direct pain) and von Frey analysis at the footpad (to assess tactile allodynia from collateral innervation). Once painful neuromas were detected 6 weeks later, animals were randomized to experimental groups: (a) TMR to the motor branch to biceps femoris, (b) RPNI with an extensor digitorum longus graft, (c) neuroma excision, and (d) neuroma in situ. The TMR/RPNIs were harvested to confirm muscle reinnervation, and the sensory ganglia and nerves were harvested to assess markers of regeneration, pain, and inflammation. RESULTS: Ten weeks post-TMR/RPNI surgery, animals had decreased pain scores compared with controls ( P < .001) and they both demonstrated neuromuscular junction reinnervation. Compared with neuroma controls, immunohistochemistry showed that sensory neuronal cell bodies of TMR and RPNI showed a decrease in regeneration markers phosphorylated cyclic AMP receptor binding protein and activation transcription factor 3 and pain markers transient receptor potential vanilloid 1 and neuropeptide Y ( P < .05). The nerve and dorsal root ganglion maintained elevated Iba-1 expression in all cohorts. CONCLUSION: RPNI and TMR improved pain scores after neuroma resection suggesting both may be clinically feasible techniques for improving outcomes for patients with nerve injuries or those undergoing amputation.

Reverse End-to-Side Nerve Transfer for Severe Ulnar Nerve Injury: A Western Canadian Multicentre Prospective Nonrandomized Cohort Study.

BACKGROUND: Reverse end-to-side (RETS) nerve transfer has become increasingly popular in patients with severe high ulnar nerve injury, but the reported outcomes have been inconsistent. OBJECTIVE: To evaluate the "babysitting effect," we compared outcomes after anterior interosseous nerve RETS transfer with nerve decompression alone. To evaluate the source of regenerating axons, a group with end-to-end (ETE) transfer was used for comparisons. METHODS: Electrophysiology measures were used to quantify the regeneration of anterior interosseous nerve (AIN) and ulnar nerve fibers while functional recovery was evaluated using key pinch and Semmes-Weinstein monofilaments. The subjects were followed postsurgically for 3 years. RESULTS: Sixty-two subjects (RETS = 25, ETE = 16, and decompression = 21) from 4 centers in Western Canada were enrolled. All subjects with severe ulnar nerve injury had nerve compression at the elbow except 10 in the ETE group had nerve laceration or traction injury. Postsurgically, no reinnervation from the AIN to the abductor digiti minimi muscles was seen in any of the RETS subjects. Although there was no significant improvement in compound muscle action potentials amplitudes and pressure detection thresholds in the decompression and RETS group, key pinch strength significantly improved in the RETS group ( P < .05). CONCLUSION: The results from published clinical trials are conflicting in part because crossover regeneration from the donor nerve has never been measured. Unlike those with ETE nerve transfers, we found that there was no crossover regeneration in the RETS group. The extent of reinnervation was also no different from decompression surgery alone. Based on these findings, the justifications for this surgical technique need to be carefully re-evaluated.

A new method to quantify innervation of the ulnar intrinsic hand muscles by the anterior interosseous nerve in Martin-Gruber anastomosis and nerve transfer surgery.

INTRODUCTION/AIMS: It is important to quantify the amount of crossover innervation from the anterior interosseous nerve (AIN) through Martin-Gruber anastomosis (MGA) particularly in patients with high ulnar nerve injury who undergo nerve transfer surgery. The objective of this study is to describe a novel electrophysiological method for quantifying innervation from the AIN that can be done using conventional nerve conduction study setup and commonly available software for analysis. METHODS: Seven subjects with MGA and nine patients who had undergone AIN to ulnar nerve transfer underwent conventional motor nerve conduction studies. Recording was done over the hypothenar and first dorsal interosseous muscles while stimulating the median and ulnar nerves at the wrist and elbow. Datapoint-by-datapoint subtraction of the compound muscle action potentials evoked at the elbow and wrist was performed after they had been onset-aligned. The results were compared to the collision technique and innervation ratio method. RESULT: Results from the digital subtraction method were highly correlated with the collision technique (r = 0.96, p < 0.05). In contrast, its correlation with the innervation ratio method is substantially lower. DISCUSSION: In comparison to previously described techniques, the digital subtraction method has a number of practical advantages. It uses conventional nerve conduction study setup, and the added step of digital alignment and subtraction can be done through commonly available software. With the increasing use of nerve transfer surgery in severe high ulnar nerve injury, this could be a useful method to identify the presence of MGA prior to surgery and for evaluating nerve recovery following surgery.

Recovering the regenerative potential in chronically injured nerves by using conditioning electrical stimulation.

OBJECTIVE: Chronically injured nerves pose a significant clinical challenge despite surgical management. There is no clinically feasible perioperative technique to upregulate a proregenerative environment in a chronic nerve injury. Conditioning electrical stimulation (CES) significantly improves sensorimotor recovery following acute nerve injury to the tibial and common fibular nerves. The authors' objective was to determine if CES could foster a proregenerative environment following chronically injured nerve reconstruction. METHODS: The tibial nerve of 60 Sprague Dawley rats was cut, and the proximal ends were inserted into the hamstring muscles to prevent spontaneous reinnervation. Eleven weeks postinjury, these chronically injured animals were randomized, and half were treated with CES proximal to the tibial nerve cut site. Three days later, 24 animals were killed to evaluate the effects of CES on the expression of regeneration-associated genes at the cell body (n = 18) and Schwann cell proliferation (n = 6). In the remaining animals, the tibial nerve defect was reconstructed using a 10-mm isograft. Length of nerve regeneration was assessed 3 weeks postgrafting (n = 16), and functional recovery was evaluated weekly between 7 and 19 weeks of regeneration (n = 20). RESULTS: Three weeks after nerve isograft surgery, tibial nerves treated with CES prior to grafting had a significantly longer length of nerve regeneration (p < 0.01). Von Frey analysis identified improved sensory recovery among animals treated with CES (p < 0.01). Motor reinnervation, assessed by kinetics, kinematics, and skilled motor tasks, showed significant recovery (p < 0.05 to p < 0.001). These findings were supported by immunohistochemical quantification of motor endplate reinnervation (p < 0.05). Mechanisms to support the role of CES in reinvigorating the regenerative response were assessed, and it was demonstrated that CES increased the proliferation of Schwann cells in chronically injured nerves (p < 0.05). Furthermore, CES upregulated regeneration-associated gene expression to increase growth-associated protein-43 (GAP-43), phosphorylated cAMP response element binding protein (pCREB) at the neuronal cell bodies, and upregulated glial fibrillary acidic protein expression in the surrounding satellite glial cells (p < 0.05 to p < 0.001). CONCLUSIONS: Regeneration following chronic axotomy is impaired due to downregulation of the proregenerative environment generated following nerve injury. CES delivered to a chronically injured nerve influences the cell body and the nerve to re-upregulate an environment that accelerates axon regeneration, resulting in significant improvements in sensory and motor functional recovery. Percutaneous CES may be a preoperative strategy to significantly improve outcomes for patients undergoing delayed nerve reconstruction.

Brachial Plexus Reconstruction Using Long Nerve Grafts as Spare Parts From an Amputated Limb: A Case Report.

CASE: The reconstruction of large nerve gaps remains a reconstructive challenge. Here, we present a case report of brachial plexus reconstruction using nerve grafts harvested as spare parts from an amputated limb. It also allowed us to use motor nerve grafts to reconstruct defects in the posterior cord and musculocutaneous nerve. The patient recovered good shoulder and elbow function at 2.5 years with evidence of innervation distally on electromyography. CONCLUSION: Spare part surgery should always be kept in a surgeons' reconstructive algorithm. Reconstruction of large nerve gaps can be achieved with autologous nerve grafts in certain circumstances.

Impacts of Rehabilitation Gait Training on Functional Outcomes after Tibial Nerve Transfer for Patients with Peroneal Nerve Injury: A Nonrandomized Controlled Trial.

BACKGROUND: Although there was initial success using tibial nerve transfer to restore ankle dorsiflexion following peroneal nerve injury, results from later series were less promising. A potential reason is coactivation of the much stronger antagonistic muscles during gait. The purpose of this study was to test the hypothesis that gait training would improve functional performance following tibial nerve transfer. METHODS: Using a prospective, nonrandomized, controlled study design, patients were divided into two groups: surgery only or surgery plus gait training. Of the 20 patients who showed reinnervation in the tibialis anterior muscle, 10 were assigned to the gait training group, and an equal number were in the control group. Those in the treatment group began training once reinnervation in the tibialis anterior muscle was detected, whereas those in the control group continued to use their ankle-foot orthosis full time. Differences in ankle dorsiflexion were measured using the Medical Research Council scale, and quantitative force measurement and functional disability was measured using the Stanmore Scale. RESULTS: Patients in the gait training group attained significantly better functional recovery as measured by the Stanmore Scale (79.5 ± 14.3) (mean ± SD) versus (37.2 ± 3.5) in the control group (p = 0.02). Medical Research Council grades were 3.8 ± 0.6 in the training group versus 2.5 ± 1.2 in the surgery only group (p < 0.05). Average dorsiflexion force from patients with above antigravity strength (all from the training group) was 31 percent of the contralateral side. CONCLUSION: In patients with successful reinnervation following tibial nerve transfers, rehabilitation training significantly improved dorsiflexion strength and function. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, II.

Electrical stimulation to enhance peripheral nerve regeneration: Update in molecular investigations and clinical translation.

Peripheral nerve injuries are common and frequently result in incomplete functional recovery even with optimal surgical treatment. Permanent motor and sensory deficits are associated with significant patient morbidity and socioeconomic burden. Despite substantial research efforts to enhance peripheral nerve regeneration, few effective and clinically feasible treatment options have been found. One promising strategy is the use of low frequency electrical stimulation delivered perioperatively to an injured nerve at the time of surgical repair. Possibly through its effect of increasing intraneuronal cyclic AMP, perioperative electrical stimulation accelerates axon outgrowth, remyelination of regenerating axons, and reinnervation of end organs, even with delayed surgical intervention. Building on decades of experimental evidence in animal models, several recent, prospective, randomized clinical trials have affirmed electrical stimulation as a clinically translatable technique to enhance functional recovery in patients with peripheral nerve injuries requiring surgical treatment. This paper provides an updated review of the cellular physiology of electrical stimulation and its effects on axon regeneration, Level I evidence from recent prospective randomized clinical trials of electrical stimulation, and ongoing and future directions of research into electrical stimulation as a clinically feasible adjunct to surgical intervention in the treatment of patients with peripheral nerve injuries.

Conditioning Electrical Stimulation Accelerates Regeneration in Nerve Transfers.

OBJECTIVE: Compared to the upper limb, lower limb distal nerve transfer (DNT) outcomes are poor, likely due to the longer length of regeneration required. DNT surgery to treat foot drop entails rerouting a tibial nerve branch to the denervated common fibular nerve stump to reinnervate the tibialis anterior muscle for ankle dorsiflexion. Conditioning electrical stimulation (CES) prior to nerve repair surgery accelerates nerve regeneration and promotes sensorimotor recovery. We hypothesize that CES prior to DNT will promote nerve regeneration to restore ankle dorsiflexion. METHODS: One week following common fibular nerve crush, CES was delivered to the tibial nerve in half the animals, and at 2 weeks, all animals received a DNT. To investigate the effects of CES on nerve regeneration, a series of kinetic, kinematic, skilled locomotion, electrophysiologic, and immunohistochemical outcomes were assessed. The effects of CES on the nerve were investigated. RESULTS: CES-treated animals had significantly accelerated nerve regeneration (p < 0.001), increased walking speed, and improved skilled locomotion. The injured limb had greater vertical peak forces, with improved duty factor, near-complete recovery of braking, propulsive forces, and dorsiflexion (p < 0.01). Reinnervation of the tibialis anterior muscle was confirmed with nerve conduction studies and immunohistochemical analysis of the neuromuscular junction. Immunohistochemistry demonstrated that CES does not induce Wallerian degeneration, nor does it cause macrophage infiltration of the distal tibial nerve. INTERPRETATION: Tibial nerve CES prior to DNT significantly improved functional recovery of the common fibular nerve and its muscle targets without inducing injury to the donor nerve. ANN NEUROL 2020;88:363-374.

Conditioning Electrical Stimulation Is Superior to Postoperative Electrical Stimulation in Enhanced Regeneration and Functional Recovery Following Nerve Graft Repair.

Background. Autologous nerve graft is the most common clinical intervention for repairing a nerve gap. However, its regenerative capacity is decreased in part because, unlike a primary repair, the regenerating axons must traverse 2 repair sites. Means to promote nerve regeneration across a graft are needed. Postoperative electrical stimulation (PES) improves nerve growth by reducing staggered regeneration at the coaptation site whereas conditioning electrical stimulation (CES) accelerates axon extension. In this study, we directly compared these electrical stimulation paradigms in a model of nerve autograft repair. Methods. To lay the foundation for clinical translation, regeneration and reinnervation outcomes of CES and PES in a 5-mm nerve autograft model were compared. Sprague-Dawley rats were divided into: (a) CES, (b) PES, and (c) no stimulation cohorts. CES was delivered 1 week prior to nerve cut/coaptation, and PES was delivered immediately following coaptation. Length of nerve regeneration (n = 6/cohort), and behavioral testing (n = 16/cohort) were performed at 14 days and 6 to 14 weeks post-coaptation, respectively. Results. CES treated axons extended 5.9 ± 0.2 mm, significantly longer than PES (3.8 ± 0.2 mm), or no stimulation (2.5 ± 0.2 mm) (P < .01). Compared with PES animals, the CES animals had significantly improved sensory recovery (von Frey filament testing, intraepidermal nerve fiber reinnervation) (P < .001) and motor reinnervation (horizontal ladder, gait analysis, nerve conduction studies, neuromuscular junction analysis) (P < .01). Conclusion. CES resulted in faster regeneration through the nerve graft and improved sensorimotor recovery compared to all other cohorts. It is a promising treatment to improve outcomes in patients undergoing nerve autograft repair.

The Triceps Traction Test: A Decision Tool for the Choice of Stabilizing Flap After In Situ Decompression of the Ulnar Nerve.

PURPOSE: Recent evidence demonstrates that in situ decompression has comparable outcomes to other surgical techniques for cubital tunnel syndrome. However, this technique does not address the instability of the ulnar nerve, a common indication to transpose the ulnar nerve. Transposition of the ulnar nerve can potentially devascularize the ulnar nerve, stabilizing flaps block subluxation of the ulnar nerve and thereby negate the need for transposition. Flaps originating from the triceps and the flexor-pronator fascia could be used to stabilize the ulnar nerve. Herein, we present a novel intraoperative test, the "triceps traction test" and our algorithm for choosing a stabilizing flap when ulnar nerve instability is encountered after in situ decompression.

Postsurgical Electrical Stimulation Enhances Recovery Following Surgery for Severe Cubital Tunnel Syndrome: A Double-Blind Randomized Controlled Trial.

BACKGROUND: Patients with severe cubital tunnel syndrome often have poor functional recovery with conventional surgical treatment. Postsurgical electrical stimulation (PES) has been shown to enhance axonal regeneration in animal and human studies. OBJECTIVE: To determine if PES following surgery for severe cubital tunnel syndrome would result in better outcomes compared to surgery alone. METHODS: Patients with severe cubital tunnel syndrome in this randomized, double-blind, placebo-controlled trial were randomized in a 1:2 ratio to the control or stimulation groups. Control patients received cubital tunnel surgery and sham stimulation, whereas patients in the stimulation group received 1-h of 20 Hz PES following surgery. Patients were assessed by a blinded evaluator annually for 3 yr. The primary outcome was motor unit number estimation (MUNE) and secondary outcomes were grip and key pinch strength and McGowan grade and compound muscle action potential. RESULTS: A total of 31 patients were enrolled: 11 received surgery alone and 20 received surgery and PES. Three years following surgery, MUNE was significantly higher in the PES group (176 ± 23, mean + SE) compared to controls (88 ± 11, P < .05). The mean gain in key pinch strength in the PES group was almost 3 times greater than in the controls (P < .05). Similarly, other functional and physiological outcomes showed significantly greater improvements in the PES group. CONCLUSION: PES enhanced muscle reinnervation and functional recovery following surgery for severe cubital tunnel syndrome. It may be a clinically useful adjunct to surgery for severe ulnar neuropathy, in which functional recovery with conventional treatment is often suboptimal.

Laterality and risk factors for ulnar neuropathy at the elbow.

BACKGROUND: Ulnar neuropathy at the elbow (UNE) is the second commonest entrapment neuropathy after carpal tunnel syndrome (CTS) and yet the laterality is not well delineated. Our aim was to establish the laterality of UNE in a large cohort of patients. METHODS: All new patients with clinical and electrodiagnostic (EDX) confirmed UNE over a 13-year period were included. We used multivariate analysis to examine potential predictors of laterality, and unilateral vs bilateral UNE. RESULTS: Of 880 cases, 61% were left-sided and 39% right-sided. These proportions did not change regardless of the handedness of the patient. Patients with bilateral UNE were much more likely to be older male and have a variety of comorbidities. CONCLUSIONS: UNE appears to be present on the left 50% more often than on the right, regardless of the patient's handedness.

Conditioning electrical stimulation is superior to postoperative electrical stimulation, resulting in enhanced nerve regeneration and functional recovery.

Postoperative electrical stimulation (PES) improves nerve regeneration by decreasing staggered regeneration at the coaptation site. By contrast, conditioning (preoperative) electrical stimulation (CES) accelerates axon extension. Given that both techniques can be delivered at the bedside, a direct comparison of outcomes is of significant clinical importance. In this study, we compared regeneration and reinnervation outcomes of CES, PES, a combination of CES and PES, and a no stimulation control. Sprague Dawley rats were randomly divided into i) CES, ii) PES, iii) CES + PES, and iv) no stimulation. CES was delivered one week prior to nerve cut/coaptation, and PES was delivered immediately following nerve repair. Length of nerve regeneration was assessed at 7 days post-coaptation (n = 6/cohort), and behavioral testing was performed between 6 and 8 weeks post-coaptation (n = 8/cohort). Animals treated with CES had significantly longer axon extension and improved sensorimotor recovery compared to all other cohorts. CES treated axons extended 8.5 ± 0.6 mm, significantly longer than PES (5.5 ± 0.5 mm), CES + PES (3.6 ± 0.7 mm), or no stimulation (2.7 ± 0.5 mm) (p < .001). Sensory recovery (von Frey filament testing, intraepidermal nerve fiber reinnervation) (p < .001) and motor reinnervation (horizontal ladder, gait analysis, nerve conduction studies, neuromuscular junction analysis) (p < .05 - p < .001) were significantly improved in CES animals. CES significantly improves regeneration and reinnervation beyond the current clinical paradigm of PES. The combination of CES and PES does not have a synergistic effect. CES alone therefore may be a more promising treatment to improve outcomes in patients undergoing nerve repair surgeries.